Novel solubility-switchable MRI agent allows the noninvasive detection of matrix metalloproteinase-2 activity in vivo in a mouse model.
A novel MRI proteinase-modulated contrast agent (PCA) was developed to detect the activity of the proinvasive enzyme matrix metalloproteinase-2 (MMP-2) in vivo. The PCA2-switch agent incorporates a solubility switch, where cleavage of a peptide substrate by MMP-2 decreases the water solubility of the agent. Evidence suggests that this leads to an accumulation of cleaved PCA2-switch in an MMP-2-positive, wild-type, MC7-L1 mammary carcinoma tumor in a Balb/c mouse model compared to a MC7-L1 MMP-2-knockdown tumor. When a scrambled peptide sequence is inserted into the agent (PCA2-scrambled), the in vitro cleavage efficiency of MMP-2 is markedly reduced. In vivo, PCA2-scrambled does not accumulate in the wild-type tumor and the pharmacokinetics is similar in both tumors. In conclusion, in vivo cleavage of PCA2-switch by MMP-2 results in a significant accumulation of the cleaved PCA2-switch in an MMP-2-positive tumor.
Lebel
Réjean
R
Département de Médecine Nucléaire et de Radiobiologie, Centre d'Imagerie Moléculaire de Sherbrooke, Université de Sherbrooke, Sherbrooke, Québec, Canada.
Jastrzebska
Beata
B
Therriault
Hélène
H
Cournoyer
Marie-Michèle
MM
McIntyre
J Oliver
JO
Escher
Emanuel
E
Neugebauer
Witold
W
Paquette
Benoit
B
Lepage
Martin
M
D000818:Animals; D045744:Cell Line, Tumor; D003287:Contrast Media / Q000493:pharmacokinetics; D004789:Enzyme Activation; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D010447:Peptide Hydrolases / Q000493:pharmacokinetics*
D003287:Contrast Media; D010447:Peptide Hydrolases; D020778:Matrix Metalloproteinase 2